Human Papillomavirus DNA Methylation as a Biomarker for Cervical Precancer: Consistency across 12 Genotypes and Potential Impact on Management of HPV-Positive Women
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- Megan A. Clarke
- 1Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD, USA.
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- Ana Gradissimo
- 2Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York.
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- Mark Schiffman
- 1Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD, USA.
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- Jessica Lam
- 2Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York.
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- Christopher C. Sollecito
- 2Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York.
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- Barbara Fetterman
- 3Regional Laboratory, The Permanente Medical Group, Oakland, California.
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- Thomas Lorey
- 3Regional Laboratory, The Permanente Medical Group, Oakland, California.
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- Nancy Poitras
- 3Regional Laboratory, The Permanente Medical Group, Oakland, California.
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- Tina R. Raine-Bennett
- 4Kaiser Permanente Division of Research, Oakland, California.
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- Philip E. Castle
- 5Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York.
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- Nicolas Wentzensen
- 1Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD, USA.
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- Robert D. Burk
- 6Departments of Epidemiology and Population Health, Microbiology and Immunology, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York.
説明
<jats:title>Abstract</jats:title> <jats:p>Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated.</jats:p> <jats:p>Experimental Design: In this nested case–control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.</jats:p> <jats:p>Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.</jats:p> <jats:p>Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194–202. ©2018 AACR.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 24 (9), 2194-2202, 2018-04-30
American Association for Cancer Research (AACR)